Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

• the invention relates to new N-substituted azabicydoheptane derivatives, their preparation and use for disease control.
• Exo-6-phenyl-3-azabicyclo [3.2.0] heptane derivatives have interesting properties as potential neuroleptics (WO 94/00458, WO 95/15312).
• the observed high affinities for D 4 and 5-HT 2 receptors play a special role here.
• WO 96/04272 describes N-substituted 3-azabtcycto [3.2.0] heptane derivatives and whose properties are described as neuroleptics.
• the compounds of formula I according to the invention can be prepared by using a compound of formula II in which R 2 and R 3 have the meanings given above and Nu represents a nucleofugic leaving group, with a 3-azabicyclo- [3.2.0] heptane derivative of the formula III as (+) - (1S, 5R, exo-6S) enantiomer wherein R 1 has the meaning given above, and the compound thus obtained is optionally converted into the acid addition salt of a physiologically acceptable acid.
• Halogen atoms in particular bromine or chlorine, are preferably used as the nucleofugic leaving group for Nu.
• the reaction is advantageously carried out in the presence of an inert base, such as triethylamine or potassium carbonate, as an acid-binding agent in an inert solvent, such as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or a benzene hydrocarbon, such as toluene or xylene.
• an inert base such as triethylamine or potassium carbonate
• an inert solvent such as a cyclic saturated ether, in particular tetrahydrofuran or dioxane, or a benzene hydrocarbon, such as toluene or xylene.
• the reaction is usually carried out at temperatures from 20 to 150 ° C, especially from 80 to 140 ° C, and is in general finished within 1 to 10 hours.
• the compounds of formula I according to the invention can either by recrystallization from the usual organic solvents, preferably recrystallized from a lower alcohol, such as ethanol or purified by column chromatography.
• the free 3-azabicyclo [3.2.0] heptane derivatives of the formula I can in the usual way in the acid addition salt of a pharmacologically tolerated acid, preferably by transfer a solution with an equivalent of the corresponding Acid.
• pharmaceutically acceptable acids are Hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, Amidosulfonic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid or citric acid.
• the compounds according to the invention have valuable pharmacological Properties on. They can be used as neuroleptics (especially atypical), antidepressants, sedatives, hypnotics, CNS protectives or agents to treat cocaine addiction Find use. Several of the effectiveness qualities mentioned can occur in combination in a compound according to the invention.
• the substances are particularly characterized by a very high and selective affinity for the dopamine D 4 and serotonin 2A receptor.
• the invention also relates to a therapeutic agent, characterized in that it contains a compound of the formula I or its pharmacologically tolerable acid addition salt as active ingredient in addition to conventional carriers and diluents, and the use of the new compounds in combating diseases.
• the compounds according to the invention can be administered in the usual way orally or parenterally, intravenously or intramuscularly.
• the dosage depends on the age, condition and weight of the patient as well as on the type of application.
• the daily is Active ingredient dose between about 1 and 100 mg / kg body weight with oral administration and between 0.1 and 10 mg / kg body weight parenteral administration.
• the new compounds can be used in common galenical application forms in solid or liquid form, for example as tablets, film-coated tablets, capsules, powders, granules, dragees, suppositories, solutions, ointments, creams or sprays. These are manufactured in the usual way.
• the active ingredients can be processed with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants (see H. Sucker et. Al: Pharmaceuticals Technology, Thieme-Verlag, Stuttgart, 1978).
• the application forms thus obtained normally contain the active ingredient in an amount of 1 to 99% by weight.
• the aqueous phase was extracted again with methyl tert-butyl ether and the concentrated organic phases were then concentrated.
• the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride / methanol 97/3. 3.3 g (71%) of product were isolated as an oil, which was dissolved in 200 ml of ether and with 1.4 g (9.3 mM) of tartaric acid , dissolved in ethanol, into which tartrate (mp. 107 to 109 ° C.) was converted.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Anesthesiology (AREA)
• Addiction (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Indole Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Priority Applications (1)

Applications Claiming Priority (3)

Publications (2)

Family

ID=7877215

Family Applications (1)

Country Status (27)

Family Cites Families (6)

• 1998
  • 1998-08-12 DE DE19836404A patent/DE19836404A1/de not_active Withdrawn
• 1999
  • 1999-07-20 SK SK81-2001A patent/SK812001A3/sk unknown
  • 1999-07-20 JP JP2000564951A patent/JP2002522538A/ja active Pending
  • 1999-07-20 KR KR1020017001780A patent/KR20010072407A/ko not_active Application Discontinuation
  • 1999-07-20 CZ CZ2001465A patent/CZ2001465A3/cs unknown
  • 1999-07-20 ID IDW20010348A patent/ID27964A/id unknown
  • 1999-07-20 HU HU0103099A patent/HUP0103099A3/hu unknown
  • 1999-07-20 AT AT99942792T patent/ATE239015T1/de not_active IP Right Cessation
  • 1999-07-20 CA CA002340168A patent/CA2340168A1/en not_active Abandoned
  • 1999-07-20 TR TR2001/00476T patent/TR200100476T2/xx unknown
  • 1999-07-20 WO PCT/EP1999/005166 patent/WO2000009499A1/de not_active Application Discontinuation
  • 1999-07-20 AU AU56186/99A patent/AU5618699A/en not_active Abandoned
  • 1999-07-20 DK DK99942792T patent/DK1105388T3/da active
  • 1999-07-20 EP EP99942792A patent/EP1105388B1/de not_active Expired - Lifetime
  • 1999-07-20 BR BR9912888-8A patent/BR9912888A/pt not_active IP Right Cessation
  • 1999-07-20 IL IL14091999A patent/IL140919A0/xx unknown
  • 1999-07-20 ES ES99942792T patent/ES2198947T3/es not_active Expired - Lifetime
  • 1999-07-20 CN CN99809525A patent/CN1312808A/zh active Pending
  • 1999-07-20 DE DE59905342T patent/DE59905342D1/de not_active Expired - Fee Related
  • 1999-07-20 PL PL99346003A patent/PL346003A1/xx not_active Application Discontinuation
  • 1999-07-20 PT PT99942792T patent/PT1105388E/pt unknown
  • 1999-08-12 MY MYPI99003450A patent/MY133139A/en unknown
  • 1999-08-12 CO CO99051371A patent/CO5130037A1/es unknown
• 2001
  • 2001-02-06 NO NO20010624A patent/NO20010624L/no not_active Application Discontinuation
  • 2001-03-09 BG BG105329A patent/BG105329A/xx unknown
  • 2001-03-09 ZA ZA200101971A patent/ZA200101971B/en unknown
  • 2001-03-12 HR HR20010181A patent/HRP20010181A2/hr not_active Application Discontinuation
• 2002
  • 2002-03-07 HK HK02101761.3A patent/HK1040082A1/zh unknown

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